Analysis of Noelin, a Neural Crest Competence Factor

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DESCRIPTION (provided by the applicant): The vertebrate neural crest appears to form via an inductive interaction between the non-neural ectoderm and the neural plate, thus requiring both a source of inducer (the ectoderm) and a competent receiving tissue (the neural plate). Molecules expressed in the early neural plate may be involved in rendering the tissue "competent" to respond to neural crest induction. By screening neural crest/tube libraries, we have identified a secreted factor, Noelin-1, which is expressed in the prospective avian neural plate and may play a role in making the neural tube competent to form neural crest. Noelin-1 mRNA predicts a protein with a signal peptide, N-glycosylation sites and an olfactomedin-related domain; it is secreted when over-expressed in frog oocytes. Noelin-1 mRNA is expressed in a graded pattern in the closing neural tube, with highest expression in the neural folds and no detectable expression at the ventral midline. The proposed experiments will extend the preliminary findings to further characterize the role of Noelin-1 in early embryonic development. Our working premise is that Noelin-1 bestows competence onto neural tube cells to form neural crest. Noelin is expressed in the intermediate neural plate at a time that correlates with the neural plate's ability to respond to induction by the non-neural ectoderm. Recent work from our laboratory suggests that Wnts may be the initial neural crest inducers and that BMPs may function later to maintain/expand newly-induced neural crest population. Thus, Noelin promises to be a particularly exciting factor since little is known about biological properties underlying tissue competence and how competence factors interact with inducers. We hypothesize that: (1) Noelin-1 renders the neural plate competent to respond to an inductive signal from the surface ectoderm by functioning as a co-receptor; (2) maintenance of neural crest markers in the dorsal neural tube may involve a combination of Noelin plus BMP or other neural tube signals; and (3) Noelin expression is repressed by ventral neural tube signals like Sonic hedgehog. We will test these hypotheses by isolating Noelin binding partners, determining its functional requirements and analyzing the tissue/cellular interactions that mediate its expression. The goal of this proposal is to further characterize the function of Noelin-1 at the molecular and cellular level. Specific experiments will: (1) Determine the nature of molecules that interact with Noelin-1. (2) Determine the function of Noelin in imparting competence to neural tube cells to generate neural crest. (3) Generate and characterize the phenotype of Noelin-1 null mutant. (4) Examine the environmental regulation of Noelin-1 expression.